P665: RAPID AND DEEP RESPONSES WITH ASCIMINIB IN PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP) AFTER ≥2 PRIOR TYROSINE KINASE INHIBITORS (TKIS) IN THE PHASE 3 ASCEMBL STUDY
Authors: Timothy Hughes, Delphine Rea, Carla Boquimpani, Yosuke Minami, Michael Mauro, Jorge Cortes, Jane Apperley, Valentin Garcia Gutierrez, Shruti Kapoor, Meryem Ktiouet-Dawson, Vishal Dhamal, Andreas Hochhaus
Journal: HemaSphere (2023)

Background: In ASCEMBL, after ≥2 y of follow-up, asciminib (ASC) continued to demonstrate superior efficacy and better safety and tolerability than bosutinib (BOS), with more pts on ASC remaining on and continuing to benefit from therapy over time. In a preplanned subgroup analysis, major molecular response (MMR) was consistently higher with ASC than BOS across major demographic/prognostic subgroups. Aims: Characterize the efficacy of ASC over time and compared with BOS through exploratory analyses in ASCEMBL. Methods: Eligible pts with intolerance or treatment failure/lack of efficacy per European LeukemiaNet (ELN) 2013 recommendations were randomized 2:1 to ASC 40 mg twice daily or BOS 500 mg once daily and gave informed consent. Per ELN 2013, pts with BCR::ABL1IS >10% at wk 24 were considered to have lack of efficacy and discontinued therapy. Analyses included: molecular response at different times according to baseline (BL) BCR::ABL1IS; cumulative incidence of MMR/BCR::ABL1IS ≤1% in nonresponders by wk 24; MMR rate at wk 96 according to prior TKIs and reason for discontinuation and by number of prior 2nd generation (2G) TKIs; cumulative incidence of MMR by BL BCR::ABL1IS, reason for prior TKI discontinuation, and line of randomized therapy (data cutoff: October 6, 2021). Results: Of 60 pts on ASC with BCR::ABL1IS ≤10% at BL, 18 (30.0%), 24 (40.0%), and 36 (60.0%) reached MMR at wk 12, 24, and 96, respectively, and 38 (63.3%), 45 (75.0%), and 47 (78.3%) reached BCR::ABL1IS ≤1%, respectively; of 97 pts with BCR::ABL1IS >10% at BL, 10 (10.3%), 16 (16.5%), and 23 (23.7%) reached MMR, respectively, and 28 (28.9%), 32 (33.0%), and 29 (29.9%) reached BCR::ABL1IS ≤1%, respectively. 23 pts (14.6%) had BCR::ABL1IS >10% at wk 24 and discontinued treatment per protocol. Of 18 pts on ASC with BCR::ABL1IS >1% by wk 24 who were still on ASC after wk 24, the probability of BCR::ABL1IS ≤1% (95% CI) was 22.2% (6.5%-43.6%) by 1 y and 38.9% (16.4%-61.0%) by 2 y. Of 56 pts on ASC without MMR by wk 24 who were still on ASC after wk 24, the probability of MMR (95% CI) was 17.9% (9.1%-29.0%) by 1 y and 37.9% (25.1%-50.6%) by 2 y, demonstrating that pts who continued ASC beyond wk 24 could achieve MMR at later time points. Overall MMR rates at wk 96 were higher with ASC than BOS regardless of the last prior TKI received (imatinib, 55.6% vs 14.3%; nilotinib, 40.9% vs 35.7%; dasatinib, 37.1% vs 10.5%; radotinib, 50.0% vs 0%; ponatinib, 20.0% vs 11.8%) and reason for its discontinuation (intolerance [ASC, n=59; BOS, n=22] vs resistance [ASC, n=95; BOS, n=54]). A higher proportion of pts resistant to all prior 2G TKIs achieved MMR with ASC vs BOS, respectively, at wk 96: 34.3% vs 7.7% (1 prior 2G TKI); 35.0% vs 16.7% (≥2 prior 2G TKIs). Cumulative incidence of MMR increased in both arms despite BL BCR::ABL1IS (≥10% or <10%) yet was consistently higher with ASC than BOS (Figure). The cumulative incidence of MMR was also higher with ASC than BOS by wk 96 in pts who discontinued their prior TKI due to lack of efficacy (33.2% vs 9.4%) and by line of randomized therapy (third line: 45.9% vs 33.3%; fourth line: 40.9% vs 24.8%). Summary/Conclusion: Responses were fast with ASC and continued to deepen over time. Pts who remained on ASC beyond wk 24 could still achieve MMR by later time points. Overall MMR rates at wk 96 were higher with ASC than BOS regardless of the last TKI and reason for its discontinuation; MMR rates were also higher with ASC in pts resistant to all prior 2G TKIs. The efficacy of ASC after treatment failure on 2G TKIs supports a new standard of care for pts with CML-CP for whom ≥2 prior TKIs have failed.Keywords: Chronic myeloid leukemia, Asciminib, Tyrosine kinase inhibitor